Calculation of protein ionization equilibria with conformational sampling: pKa of a model leucine zipper, GCN4 and barnase

The use of conformational ensembles provided by nuclear magnetic resonance (NMR) experiments or generated by molecular dynamics (MD) simulations has been regarded as a useful approach to account for protein motions in the context of pKa calculations, yet the idea has been tested occasionally. This i...

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Bibliographic Details
Published in:Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2002-01, Vol.46 (1), p.41-60
Main Authors: Gorfe, Alemayehu A., Ferrara, Philippe, Caflisch, Amedeo, Marti, Daniel N., Bosshard, Hans Rudolf, Jelesarov, Ilian
Format: Article
Language:English
Subjects:
AB zipper
barnase
cluster
coiled coil
electrostatics
ensemble
GCN4p1
molecular dynamics
NMR
salt bridge
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Summary:The use of conformational ensembles provided by nuclear magnetic resonance (NMR) experiments or generated by molecular dynamics (MD) simulations has been regarded as a useful approach to account for protein motions in the context of pKa calculations, yet the idea has been tested occasionally. This is the first report of systematic comparison of pKa estimates computed from long multiple MD simulations and NMR ensembles. As model systems, a synthetic leucine zipper, the naturally occurring coiled coil GCN4, and barnase were used. A variety of conformational averaging and titration curve‐averaging techniques, or combination thereof, was adopted and/or modified to investigate the effect of extensive global conformational sampling on the accuracy of pKa calculations. Clustering of coordinates is proposed as an approach to reduce the vast diversity of MD ensembles to a few structures representative of the average electrostatic properties of the system in solution. Remarkable improvement of the accuracy of pKa predictions was achieved by the use of multiple MD simulations. By using multiple trajectories the absolute error in pKa predictions for the model leucine zipper was reduced to as low as approximately 0.25 pKa units. The validity, advantages, and limitations of explicit conformational sampling by MD, compared with the use of an average structure and a high internal protein dielectric value as means to improve the accuracy of pKa calculations, are discussed. Proteins 2002;46:41–60. © 2001 Wiley‐Liss, Inc.
ISSN:0887-3585
1097-0134
DOI:10.1002/prot.10027